Oliver Adams successfully elucidated the structure of the M. tuberculosis MmpL3 membrane transporter using cryo-EM and this has recently been published online in Structure. This was the main aim of his PhD studies in Simon Newstead‘s group in the Department of Biochemistry here in Oxford. It is an important protein structure since although other MmpL3 […]
In this preprint we examine 14,151 clinical isolates drawn from the CRyPTIC dataset. Each isolate had its minimum inhibitory concentration (MIC) to bedaquiline and clofazimine measured and hence we were able to identify the transcription regulator Rv0678, as the current main source of elevated MICs to both these drugs. Lindsay Sonnenkalb, who is studying for her […]
In this preprint, the CRyPTIC project proposes the maximum value of minimum inhibitory concentration (MIC) for 13 different anti-TB drugs below which a sample can be considered to be ‘genotypically wild-type’. It is necessary to establish these values, called epidemiological cutoff values (ECOFFs or ECVs), so that the MICs measured can be converted into binary […]
A second Covid-19 publication I’m proud to be (a small) part of has recently published been in the New England Journal of Medicine. Given the Oxford University Hospital’s Staff Covid testing has been running for months, as described in our first publication, the team was able to show that having antibodies led to a substantially […]
The idea for this paper arose during talking over coffee at the BioExcel Alchemical Free Energy workshop in May 2019. We’d previously shown that alchemical free energy methods could successfully predict which mutations in S. aureus DHFR confer resistance to trimethoprim (and crucially, which do not). That is all well and good, but to do […]
Very pleased and proud to be included on this manuscript, which has been published in eLife (and is also available as a preprint); the observations are drawn from the large and comprehensive SARS-CoV-2 testing programme run by Oxford University Hospitals NHS Trust. I helped develop the internal website used by staff to book appointments and […]
Clinical microbiology often assumes a sample is resistant or susceptible. Making such a classification relies on applying a threshold (usually called a cutoff) to quantitative data, such as minimum inhibitory concentrations (MICs). If the MICs are strongly bimodal, then this is trivial and reproducibility is guaranteed. If the MICs are unimodal, then one is left […]
Although the population structure M. tuberculosis is clonal, one must be careful when inferring the effect of individual mutations on the effect of an antibiotic. Purely because a mutation appears to define a phylogeny does not mean it has no effect on the minimum inhibitory concentration. Read more here (Open Access).
The story behind this preprint goes back to the workshop on free energy methods run by BioExcel in Göttingen in May 2019. I gave a talk, based in part on the work I’d previously published showing how alchemical free energy methods are able to predict which mutations in S. aureus DHFR confer resistance to trimethoprim.
Our “First Reactions” article has been published in ACS Central Science. We discuss the paper, Predicting Kinase Inhibitor Resistance: Physics-Based and Data-Driven Approaches, by Matteo Aldeghi, Vytautas Gapsys and Bert de Groot, which is in the same issue of the journal. Aldeghi et al. apply a series of methods to try and predict the effect […]